PROJECT SUMMARY This Career Development Award (CDA) is designed to provide Dr. Krystle A. Lang Kuhs with the necessary skills and mentorship to develop an independent research program focused on head and neck cancer prevention. The goals of her future research program are to improve patient outcomes by using molecular markers to: a) detect head and neck cancers earlier (secondary prevention); b) improve pre-treatment risk stratification to personalize therapy based on prognosis (tertiary prevention) and; c) detect recurrences earlier when highly-curative salvage surgery is still an option (quaternary prevention). This is the natural next-step in Dr. Lang Kuhs? career given that it builds upon her strengthens in cancer prevention, basic science, epidemiology, oncogenic infections, and biomarker development. However, to achieve her career goals, Dr. Lang Kuhs will need to address 3 main gaps in her training: 1) clinical epidemiology (patient population experience and clinical cohort building); 2) biomedical informatics (use of electronic health record [EHR] data); and 3) advanced biostatistics (risk prediction modeling). This training will be obtained through coursework, seminars, experiential learning, hands on training and mentorship. Dr. Lang Kuhs will be mentored by leading experts in molecular epidemiology and cohort development (Dr. Wei Zheng), head and neck cancer immunology (Dr. Young Kim) and head and neck cancer survivorship (Dr. Barbara Murphy). The research portion of this CDA will focus on human papillomavirus-driven oropharyngeal cancer (HPV-OPC), a type of rapidly increasing head and neck cancer. While treatment of HPV-OPC is often curative, it is associated with severe morbidity. Clinical trials are underway to investigate whether de-escalation of treatment for HPV-OPC can decrease morbidity while still preserving high survival rates. However, the most significant barrier for the adoption of de-escalated treatment is the inability to identify patients at highest risk for recurrence. The objective of this research is to examine the potential utility of using HPV-specific biomarkers to identify patients at highest risk for recurrence. This research will utilize banked biospecimens and EHR data to create a clinical cohort of HPV-OPC patients to: 1) examine the association between HPV viral variants within OPC tumors and recurrence; 2) examine the association between pre-treatment HPV16 E6 seropositivity and E6 oncogene expression and risk recurrence; and 3) develop and refine protocols for expanded prospective collection of clinical data and biospecimens from OPC patients. The mentored training, hands on experience and results gained from this CDA will position Dr. Lang Kuhs to successfully compete for funding to establish an independent research program focused on developing biomarkers for the prevention of head and neck cancer.